Chiral derivative of matrine at position 14 and preparation method and application thereof

Abstract

The application provides a matrine 14-position chiral derivative, a preparation method and application thereof, and belongs to the technical field of pharmacy, and has a general structure as shown in the following formula: X=NH, O or wherein C in the formula is connected with R at one end; R is a substituted or unsubstituted phenyl, biphenyl, naphthyl, anthracene group or pyridyl; wherein the substituted group is an alkyl, halogenated group, formate group, morpholino group or trifluoromethoxy group. The matrine 14-position chiral derivative has good anticancer effect and can be used for preparation of anticancer drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a 14-chiral derivative of matrine, its preparation method and application. Background Technology

[0002] Matrine, also known as magnolol, is mainly derived from the root of the legume Sophora flavescens. It can also be extracted from Sophora tonkinensis root and Sophora flavescens seed through solvent extraction, ultrasonic extraction, and microwave extraction. It is a naturally occurring tetracyclic quinolone alkaloid containing two quinazidine rings, with the chemical formula C. 15 H 24 N₂O, with a molecular weight of 248.37, is a white powder in its pure form, and a brownish-yellow liquid or powder in low concentrations. It is soluble in water. Its structural formula is as follows:

[0003]

[0004] Matrine has a wide range of pharmacological effects, and its anti-tumor effects have attracted attention, with studies showing that it inhibits various cancer cells, such as prostate cancer, pancreatic cancer, gastric cancer, liver cancer, lung cancer, and breast cancer. However, no matrine derivatives have been found to simultaneously exhibit significant inhibitory effects against both liver and brain cancer.

[0005] Therefore, there is an urgent need to provide a matrine derivative that has a significant inhibitory effect on both liver cancer and brain cancer, and its preparation method. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention proposes a 14-chiral derivative of matrine, its preparation method, and its application. Specifically, using matrine as the starting material, under strongly alkaline bis(trimethylsilyl)aminosodium conditions, the H atom at the α-position of the matrine lactone is removed to form an α-carbanion. This α-carbanion then undergoes a nucleophilic reaction with tert-butyl nitrite to obtain the intermediate matrine oxime I. Further dehydration with hydrazine hydrate forms the intermediate matrine hydrazone II. Oxidation with manganese dioxide forms the key intermediate matrine diazo III. Finally, under the catalysis of copper tetraacetonitrile hexafluorophosphate, an insertion reaction occurs with amino, hydroxyl, and acid derivatives, followed by separation to obtain the 14-chiral derivative of matrine, which possesses strong antitumor activity.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] One of the technical solutions of the present invention:

[0009] A chiral derivative of matrine at position 14 has the following general structural formula:

[0010]

[0011] In the general formula of the structure, X = NH, O or in, C is connected to one end of R;

[0012] R is a substituted or unsubstituted phenyl, biphenyl, naphthyl, anthraceneyl, or pyridyl group; wherein the substituted group is an alkyl, haloyl, formate, morpholinyl, or trifluoromethoxy group.

[0013] Preferably, when X = 0, R is selected from any of the following structures:

[0014]

[0015] Preferably, when X = NH, R is selected from any of the following structures:

[0016]

[0017] Preferably, when When R is selected, it is chosen from any of the following structures:

[0018]

[0019] The second technical solution of the present invention:

[0020] A method for preparing a 14-position chiral derivative of matrine includes the following steps:

[0021] (1) Under strong alkaline conditions and sodium bis(trimethylsilyl)amino, matrine reacts with tert-butyl nitrite in a nucleophilic reaction to give the intermediate matrine oxime I;

[0022] (2) The intermediate matrine oxime I was dehydrated with hydrazine hydrate to obtain the intermediate matrine hydrazone II;

[0023] (3) The intermediate matrine hydrazone II undergoes an oxidation reaction with manganese dioxide to obtain the intermediate matrine diazo III;

[0024] (4) Under the catalysis of copper tetraacetonitrile hexafluorophosphate, the intermediate matrine diazo III is reacted with amine, alcohol or acid compound by insertion reaction, and then concentrated and separated to obtain the 14-chiral derivative of matrine.

[0025] Preferably, the mass-volume ratio of matrine to tert-butyl nitrite in step (1) is (5-6) g: 10 mL.

[0026] Beneficial effects: The metal catalyst (copper hexafluorophosphate tetraacetonitrile) used in step (4) of this invention is the optimal catalyst. By trying different metal catalysts such as copper acetate, palladium acetate, and silver acetate, it was finally proved that copper hexafluorophosphate tetraacetonitrile has the best catalytic effect. Specifically, the total yield is 12% when copper acetate is used as the catalyst, 5% when palladium acetate is used as the catalyst, and less than 5% when silver acetate is used as the catalyst; while the total yield is over 70% when copper hexafluorophosphate tetraacetonitrile is used as the catalyst.

[0027] Further, the specific operation of step (1) is as follows: add an appropriate amount of dry tetrahydrofuran (THF) to matrine to dissolve it, inject it into a three-necked round-bottom flask with a syringe, add 70 mL of sodium bis(trimethylsilyl)aminoacetate with a syringe, and react at room temperature for 30 min; then slowly add tert-butyl nitrite dropwise to the three-necked round-bottom flask with a syringe, and react for 2 h after the addition is complete. After the reaction is completed by TLC monitoring, concentrate under reduced pressure, use PE (petroleum ether):EA (ethyl acetate) = 1:1 as eluent, and separate the concentrate by silica gel column chromatography to obtain the intermediate matrine oxime I.

[0028] Preferably, the mass-to-volume ratio of the intermediate matrine oxime I to hydrazine hydrate in step (2) is 1 g: 6 mL.

[0029] Further, the specific operation of step (2) is as follows: add an appropriate amount of ethanol to the intermediate matrine oxime I to dissolve it, then add hydrazine hydrate and place it in an oil bath at 87°C and stir, heat and reflux for 24 hours, extract, dry, and concentrate to obtain the intermediate matrine hydrazone II.

[0030] The mass-to-volume ratio of the intermediate matrine oxime I to hydrazine hydrate is 1 g: 6 mL.

[0031] Preferably, the mass ratio of the intermediate matrine hydrazone II to manganese dioxide in step (3) is 1:4.

[0032] Further, the specific operation of step (3) is as follows: anhydrous magnesium sulfate is added to the intermediate matrine hydrazone II as a dehydrating agent to promote the reaction. The mixture is stirred at room temperature, and then manganese dioxide is added. After the reaction is completed by TLC monitoring, the mixture is filtered and concentrated under reduced pressure. DCM (dichloromethane) : MeOH (a chemical reagent of methanol) = 80 : 1 is used as the eluent. The concentrate is separated by silica gel column chromatography to obtain the intermediate matrine diazonium III.

[0033] The mass ratio of the intermediate matrine hydrazone II, anhydrous magnesium sulfate, and manganese dioxide is 1:5:4.

[0034] Preferably, the molar ratio of the intermediate matrine diazonium III to an amine, alcohol or acid compound in step (4) is (1-1.2):(1.2-1.4).

[0035] Further, step (4) is specifically operated as follows: amines, alcohols, or carboxylic acid compounds are evacuated with copper tetraacetonitrile hexafluorophosphate under nitrogen protection, and then an appropriate amount of dichloromethane is added to dissolve them using a syringe; then the intermediate matrine diazonium III is dissolved in dichloromethane and slowly injected into a round-bottom flask, and reacted under ice bath conditions for 3-4 hours. After the reaction is completed by TLC monitoring, the mixture is concentrated under reduced pressure, and the concentrate is separated by silica gel column chromatography to obtain the 14-position chiral derivative of matrine;

[0036] The molar ratio of the amine or alcohol or carboxylic acid compound, copper hexafluorophosphate tetraacetonitrile, and intermediate matrine diazonium III is (1.2-1.4):0.4:(1-1.2).

[0037] The third technical solution of the present invention:

[0038] Application of the above-mentioned 14-position chiral derivative of matrine in the preparation of anticancer drugs.

[0039] Preferably, the anticancer drug is an anti-liver cancer drug or an anti-brain cancer drug.

[0040] Compared with the prior art, the present invention has the following advantages and technical effects:

[0041] This invention discloses a method for preparing a 14-chiral derivative of matrine, which utilizes readily available raw materials, is simple to operate, simplifies the synthetic steps, employs mild reaction conditions, and yields a high product. This invention is the first to synthesize a 14-diazo compound of matrine. A chiral matrine derivative was obtained through an insertion reaction, and a single-configuration matrine 14-chiral derivative was finally obtained by column chromatography. The absolute configuration of the compound was determined by single-crystal diffraction and proton NMR spectroscopy. Furthermore, experiments show that the 14-chiral matrine derivative of this invention has a strong inhibitory effect on the proliferation of various cancer cells, and this type of compound can be used in clinical tumor treatment. Attached Figure Description

[0042] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments and descriptions of this application are used to explain this application and do not constitute an undue limitation of this application. In the drawings:

[0043] Figure 1 This is a single-crystal diffraction pattern of compound Q11 in an embodiment of the present invention;

[0044] Figure 2 This is a single-crystal diffraction pattern of compound Q12 in an embodiment of the present invention. Detailed Implementation

[0045] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0046] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0047] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0048] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0049] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0050] All raw materials used in the embodiments of this invention were obtained through commercial purchase.

[0051] The technical solution of the present invention will be further illustrated by the following embodiments.

[0052] Example 1

[0053] The reaction principle involved in the preparation of a novel 14-position chiral derivative of matrine is as follows:

[0054]

[0055] (1) The steps for preparing the intermediate matrine oxime I are as follows:

[0056] 10 g of matrine was dissolved in an appropriate amount of dry tetrahydrofuran and injected into a three-necked round-bottom flask using a syringe. 70 mL of sodium bis(trimethylsilyl)aminoacetate was then added using the syringe, and the mixture was reacted at room temperature for 30 min. Next, 20 mL of tert-butyl nitrite was slowly added dropwise to the three-necked round-bottom flask using a syringe, and the reaction was allowed to proceed for 2 h after the addition was complete. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure. Using PE:EA = 1:1 as the eluent, the concentrate was separated by silica gel column chromatography to obtain the intermediate matrine oxime I, a white solid powder, 6.68 g in yield (67%). Melting point: 151.2–151.3 °C.

[0057] The structural identification data of the intermediate matrine oxime I are as follows: 1 H NMR (600MHz, CDCl3) δ15.18(s,1H),4.29(dd,J=12.8,4.4Hz,1H),3.95(m,J=10.9,7.8,5.2 Hz,1H),3.21(t,J=12.7Hz,1H),2.94-2.73(m,2H),2.63(m,J=15.4,7.4,3.8Hz,1H),2.46(m ,J=15.2,10.9,3.9Hz,1H),2.23(m,J=13.9,7.4,5.1,4.0Hz,1H),2.13(d,J=3.0Hz,1H),2.0 7-1.92(m,2H),1.92-1.83(m,1H),1.82-1.65(m,4H),1.65-1.51(m,3H),1.50-1.39(m,3H); 13 C NMR (151MHz, CDCl3) δ160.93,142.66,63.12,57.08,57.03,53.09,42.48,41.35,35.64,27.57,26.40,26.05,24.76,20.99,20.57.

[0058] (2) The steps for preparing the intermediate matrine hydrazone II are as follows:

[0059] Take 2g of the intermediate matrine oxime I, dissolve it in an appropriate amount of ethanol, add 12mL of hydrazine hydrate, place it in an oil bath at 87℃ and stir, heat under reflux for 24h, extract, dry, and concentrate to obtain 1.6g of yellow oil, with a yield of 80%.

[0060] The structural identification data of the intermediate matrine hydrazone II are as follows: 1H NMR (500MHz, CDCl3) δ6.13(s,2H),4.34(dd,J=12.8,4.6Hz,1H),3.92(ddd,J=11.1,6.6,4.6Hz,1H),3.15(t,J =12.7Hz,1H),2.77(dddd,J=24.0,13.4,4.4,2.3Hz,3H),2.43(dddd,J=16.5,8.7,5.0Hz,1H),2.28(dddd,J=16. 4,8.4,5.2Hz,1H),2.19-2.07(m,2H),1.93(qd,J=11.8,2.9Hz,2H),1.83(dt,J=13.7,2.4Hz,1H),1.73(ddt,J =17.9,12.2,4.7Hz,2H),1.69-1.57(m,2H),1.56-1.49(m,1H),1.41(qd,J=9.3,8.9,4.6Hz,3H),1.21(s,1H).

[0061] (3) The steps for preparing the intermediate matrine diazonium III are as follows:

[0062] Take 2g of the intermediate matrine hydrazone II, add 10g of anhydrous magnesium sulfate, stir at room temperature, then add 8g of manganese dioxide, and after reacting for 10min, monitor the reaction by TLC until it is complete, filter under vacuum, concentrate under reduced pressure, use DCM:MeOH = 80:1 as eluent, and separate the concentrate by silica gel column chromatography to obtain 1.8g of golden yellow oil, with a yield of 90%.

[0063] The structural identification data of the intermediate matrine diazonium III are as follows: 1 H NMR (600MHz, CDCl3) δ4.20 (dd, J=12.8, 4.5Hz, 1H), 3.83-3.75 (m, 1H), 3.06 (t, J=12 .6Hz,1H),2.79-2.67(m,2H),2.60(dddd,J=42.2,13.7,8.1,4.8Hz,2H),2.05(d,J= 3.2Hz,1H),2.00(ddt,J=13.4,8.9,4.7Hz,1H),1.88(qd,J=12.0,2.9Hz,2H),1.76( dt,J=13.4,2.5Hz,1H),1.74-1.39(m,6H),1.35(ddq,J=14.9,8.6,4.3,3.5Hz,3H). 13C NMR (151MHz, CDCl3) δ164.24,63.69,57.21,57.18,54.23,52.36,42.97,40.73,35.58,27.61,26.50,23.88,21.11,20.66,18.34.

[0064] (4) The preparation steps of (14S)-1-aniline matrine (Q1) and (14R)-1-aniline matrine (Q2) are as follows:

[0065] Weigh 112 mg of aniline and 7.5 mg (2%) of copper tetraacetonitrile hexafluorophosphate and add them to a 100 mL round-bottom flask. After evacuation and nitrogen protection, add an appropriate amount of dichloromethane to dissolve the aniline. Weigh 275 mg of the intermediate matrine diazonium III, dissolve it in dichloromethane, and slowly inject it into the round-bottom flask. React under ice bath stirring for 4 h. After the reaction is completed by TLC monitoring, concentrate under reduced pressure. Separate the concentrate by silica gel column chromatography to obtain 118 mg of white solid (14S)-1-aniline matrine (Q1) and 128 mg of white solid (14R)-1-aniline matrine (Q2).

[0066] The yield of (14S)-1-aniline matrine (Q1) was 35%. Melting point: 162.3℃-163.2℃.

[0067] The structural identification data for (14S)-1-anilinematrine (Q1) are as follows: 1 H NMR (600MHz, CDCl3) δ7.22-7.17(m,2H),6.76(tt,J=7.3,1.1Hz,1H),6.71-6.68(m,2H),4.82(s,1H), 4.31(dd,J=12.6,4.3Hz,1H),4.03(ddd,J=10.4,6.0,3.8Hz,1H),3.87(dd,J=9.5,5.1Hz,1H),3.20(t ,J=12.5Hz,1H),2.90-2.80(m,2H),2.27-2.19(m,2H),2.07-1.89(m,5H),1.84-1.67(m,4H),1.64(dt ,J=12.6,3.5Hz,1H),1.55(tt,J=13.6,4.9Hz,1H),1.44(dtt,J=25.2,14.0,3.4Hz,4H),1.28(s,1H). 13C NMR (151MHz, CDCl3) δ169.00,147.74,129.20,118.01,113.74,64.16,57.30,57.28,54.84, 53.44,43.43,41.04,35.96,27.75,26.79,24.46,21.38,21.17,20.70.m / z:340.2366(M+1).

[0068] (14R)-1-anilinematrine (Q2), yield 38%. Melting point: 143.4℃-146.3℃.

[0069] The structural identification data for (14R)-1-anilinematrine (Q2) are as follows: 1 H NMR (600MHz, CDCl3) δ7.23-7.18(m,2H),6.77-6.72(m,1H),6.70-6.63(m,2H),5.20(s,1H) ),4.38(dd,J=12.9,4.4Hz,1H),3.89(td,J=10.1,6.1Hz,1H),3.71-3.65(m,1H),3.16(t,J =12.7Hz,1H),2.91-2.78(m,2H),2.51-2.44(m,1H),2.25(ddd,J=10.5,6.2,4.2Hz,1H),2. 11(t,J=2.8Hz,1H),2.05-1.90(m,3H),1.81-1.68(m,3H),1.68-1.41(m,8H),1.28(s,1H). 13 C NMR (151MHz, CDCl3) δ169.46,147.74,129.21,117.73,113.47,77.26,63.40,57.18,57.14, 54.87,53.74,43.99,42.21,35.34,27.74,26.69,25.92,21.18,20.76.m / z:340.2360(M+1).

[0070] Example 2

[0071] Q3 and Q4 were prepared using the preparation method described in Example 1, and their structural identification data are as follows:

[0072] Compound Q3: (14S)-1-naphthylamine matrine. Pale yellow solid, yield 36%. Melting point: 178.1℃-179.2℃. 1H NMR (500MHz, CDCl3) δ8.06-7.98 (m, 1H), 7.80 (dd, J=7.1, 2.3Hz, 1H), 7.46 (tt, J=7.0, 5.2Hz, 2H), 7.40 -7.32(m,1H),7.30(d,J=8.1Hz,1H),6.62(d,J=7.4Hz,1H),5.77(s,1H),4.36(dd,J=12.5,4.3Hz,1H), 4.18-4.08(m,1H),4.02(dd,J=10.2,5.2Hz,1H),3.27(t,J=12.5Hz,1H),2.88(dd,J=23.0,11.2Hz,2H) ,2.47-2.38(m,1H),2.27(s,1H),2.18-2.01(m,3H),2.11-1.11(m,10H),0.89(dt,J=18.0,6.5Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.24,142.85,134.37,128.42,126.29,125.85,124.88,124.71,120.79,118.26,105.00, 64.30,57.20,54.81,53.45,43.62,40.63,35.96,31.46,30.21,29.72,23.63,22.71,21.27.m / z:390.2455(M+1).

[0073] Compound Q4: (14R)-1-naphthylamine matrine. Pale yellow solid, yield 39%. Melting point: 135.1℃-136.2℃. 1H NMR (500MHz, CDCl3) δ8.11-7.89(m,1H),7.89-7.69(m,1H),7.48-7.44(m,2H),7.34(dd,J=8.2,7.4Hz,1H),7.28(d ,J=1.3Hz,1H),6.54(dt,J=7.4,1.0Hz,1H),6.08(s,1H),4.42(dd,J=12.8,4.4Hz,1H),3.92(d,J=8.5Hz,1H),3.84( q,J=4.7Hz,1H),3.22(t,J=12.7Hz,1H),2.84(dd,J=22.4,11.2Hz,2H),2.61(dq,J=11.9,7.3,5.8Hz,1H),2.32-2.2 0(m,1H),2.13-2.07(m,1H),2.04-1.90(m,3H),1.82-1.67(m,3H),1.64-1.54(m,2H),1.47(dt,J=10.5,4.1Hz,3H). 13 C NMR (126MHz, CDCl3) δ169.55,142.89,134.41,128.36,126.28,125.88,124.87,124.54,120.91,117.91,104.33, 77.33,63.39,57.11,54.71,53.75,43.96,42.23,35.30,27.72,25.89,22.72,21.16,20.70.m / z:390.2454(M+1).

[0074] Example 3

[0075] Q5 and Q6 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0076] Compound Q5: (14S)-2-aminopyridinematrine. Yellow solid, yield 38%. Melting point: 177.1℃-178.2℃. 1H NMR (500MHz, CDCl3) δ8.06 (dd, J=5.3, 1.8Hz, 1H), 7.37 (ddd, J=8.7, 7.0, 1.9Hz, 1H), 6.59-6.54 (m,1H),6.51(d,J=8.4Hz,1H),5.45(s,1H),4.27(dd,2H),4.03(ddd,J=10.9,6.0,3.2Hz,1H),3 .24-3.13(m,1H),2.83(dtdd,J=24.4,10.0,4.0,2.1Hz,3H),2.42(dtd,J=13.1,5.8,3.0Hz,1H) ,2.26-2.14(m,1H),2.14-2.04(m,1H),1.96(dtt,J=15.7,12.8,2.5Hz,3H),1.82-1.37(m,11H). 13 C NMR (126MHz, CDCl3) δ169.32,158.32,147.40,137.03,113.25,109.56,64.37,57.20,53.40, 53.05,43.37,40.50,35.87,27.55,26.56,24.29,21.48,20.92,20.43.m / z:341.2325(M+1).

[0077] Compound Q6: (14R)-2-aminopyridinematrine. Yellow-brown solid, yield 37%. Melting point: 153.7℃-156.8℃. 1 H NMR (500MHz, CDCl3) δ8.26-7.93(m,1H),7.38(ddd,J=8.7,7.0,1.9Hz,1H),6.58(ddd,J=7.1,5.1,1.0Hz ,1H),6.51(dd,J=8.4,0.9Hz,1H),5.66(d,J=3.8Hz,1H),4.37(dd,J=12.9,4.4Hz,1H),4.21(dt,J=11.9 ,4.2Hz,1H),3.87(td,J=10.7,6.2Hz,1H),3.15(t,J=12.7Hz,1H),2.97-2.78(m,2H),2.76-2.60(m,1H) ,2.26-2.20(m,1H),2.10(d,J=2.9Hz,1H),2.05-1.92(m,4H),1.81-1.40(m,11H),1.27(d,J=1.8Hz,1H). 13C NMR (126MHz, CDCl3) δ169.92,158.33,147.64,136.85,113.08,109.84,63.51,57.13,57.08,53. 68,52.91,43.89,42.02,35.22,27.58,26.61,26.10,25.77,20.98,20.57.m / z:341.2325(M+1).

[0078] Example 4

[0079] Q7 and Q8 were prepared using the method described in Example 1, and their structural identification data are as follows:

[0080] Compound Q7: (14S)-1-naphthoic acid ester matrine. Yellow solid, yield 38%. Melting point: 196.5℃-199.9℃. 1 H NMR (500MHz, CDCl3) δ8.93(dd,J=8.7,1.0Hz,1H),8.23(dd,J=7.2,1.3Hz,1H),8.01(d,J=8.2Hz,1H),7.87(dd ,J=8.2,1.2Hz,1H),7.62(ddd,J=8.5,6.8,1.4Hz,1H),7.57-7.42(m,2H),5.58(dd,J=7.6,5.0Hz,1H),4.37(d d,J=12.6,4.4Hz,1H),4.01(dt,J=11.5,5.8Hz,1H),3.19(t,J=12.6Hz,1H),2.83(dd,J=24.5,11.3Hz,2H),2. 28-2.20(m,1H),2.18(s,1H),2.10(dddt,J=12.8,8.8,6.7,3.5Hz,1H),2.03-1.84(m,3H),1.81-1.37(m,8H). 13 C NMR (126MHz, CDCl3) δ166.70,165.67,133.74,133.35,131.34,130.36,128.44,127.76,127.12,126.20,125.87,124. 48,70.22,63.91,57.17,53.27,42.61,41.54,35.61,27.59,26.53,24.19,21.40,21.05,20.58.m / z:419.2232(M+1).

[0081] Compound Q8: (14R)-1-naphthoic acid ester matrine. Yellow solid, yield 40%. Melting point: 138.5℃-139.2℃.1 H NMR (500MHz, CDCl3) δ8.97 (dd, J=8.7, 1.1Hz, 1H), 8.28 (dd, J=7.3, 1.3Hz, 1H), 8.03 (dt, J=8.3, 1.0Hz, 1H), 7.9 4-7.82(m,1H),7.63(ddd,J=8.5,6.8,1.4Hz,1H),7.57-7.45(m,2H),5.59(dd,J=12.0,5.0Hz,1H),4.40(dd,J= 12.7,4.4Hz,1H),3.91(s,1H),3.20(dt,J=23.3,8.9Hz,1H),2.84(dd,J=27.4,11.2Hz,2H),2.41-2.26(m,2H), 2.09(d,J=25.0Hz,1H),2.05-1.88(m,4H),1.76(dd,J=18.3,6.9Hz,3H),1.70-1.52(m,2H),1.52-1.34(m,4H). 13 C NMR (126MHz, CDCl3) δ167.12,166.63,133.74,133.23,131.36,130.42,128.39,127.71,127.36,126.15,125.98,124.56, 69.63,63.37,57.15,57.01,53.36,43.68,41.70,35.09,27.68,26.05,25.59,25.27,21.13,20.68.m / z:419.2230(M+1).

[0082] Example 5

[0083] Q9 and Q10 were prepared using the preparation method described in Example 1, and their structural identification data are as follows:

[0084] Compound Q9: (14S)-2-naphthoic acid ester matrine. Pale yellow oil, yield 36%. 1H NMR (500MHz, CDCl3) δ8.68 (dd, J=22.8, 1.6Hz, 1H), 8.12 (ddd, J=22.4, 8.6, 1.7Hz, 1H), 8.02-7.94 ( m,1H),7.93-7.84(m,2H),7.60(ddd,J=8.2,6.8,1.4Hz,1H),7.55(ddd,J=8.2,6.8,1.4Hz,1H),5.5 3(td,J=7.9,4.9Hz,1H),4.39(dt,J=12.6,3.9Hz,1H),4.03(dt,J=11.3,5.9Hz,1H),3.20(t,J=12. 8Hz,1H),2.94-2.78(m,2H),2.37-2.20(m,2H),2.22-1.87(m,5H),1.86-1.42(m,7H),1.28(s,1H). 13 C NMR (126MHz, CDCl3) δ165.97,165.73,135.61,132.44,131.42,129.41,128.28,128.08,127.76,127.22,126.59,125.43, 70.44,64.12,57.14,57.03,53.22,42.56,42.52,35.51,29.70,25.16,24.10,21.39,20.85,20.30.m / z:419.2224(M+1).

[0085] Compound Q10: (14R)-2-naphthoic acid ester matrine ester. Pale yellow oil, yield 37%. 1 H NMR (500MHz, CDCl3) δ8.76-8.49(m,1H),8.19-8.04(m,1H),7.97(dt,J=8.3,2.2Hz,1H),7.93-7.85 (m,2H),7.60(ddt,J=9.1,7.4,1.8Hz,1H),7.55(ddt,J=8.5,6.7,1.6Hz,1H),5.57-5.47(m,1H),4.3 9(dd,J=12.6,4.3Hz,1H),4.04(dd,J=10.8,5.9Hz,1H),3.20(q,J=13.0Hz,1H),2.87(dd,J=24.8,11 .4Hz,2H),2.29-2.21(m,1H),2.16-1.90(m,3H),1.88-1.64(m,3H),1.52-1.41(m,3H),1.28(s,1H). 13C NMR (126MHz, CDCl3) δ166.56,165.97,135.61,132.44,131.43,131.07,129.40,128.29,128.08,127.76,126.60,125.43,77. 28,70.49,62.61,57.23,57.05,52.25,43.10,42.61,35.76,29.70,27.71,25.16,21.39,21.18,20.66.m / z:419.2222(M+1).

[0086] Example 6

[0087] Q11 and Q12 were prepared using the method described in Example 1, and their structural identification data are as follows:

[0088] Compound Q11: (14S)-9-anthracite matrine, pale yellow powder, yield 27%. Melting point: 165.8℃-167.2℃. 1 H NMR (600MHz, CDCl3) δ8.52-8.44(m,3H),8.02(dd,J=8.4,1.3Hz,2H),7.54(ddd,J=8.7,6.5,1.4Hz,2H),7.48(dd d,J=7.6,6.5,1.0Hz,2H),5.86-5.73(m,2H),4.50(dd,J=12.6,4.4Hz,1H),4.16(q,J=3.0Hz,1H),3.82(dd,J=12. 1,6.5Hz,1H),3.17(t,J=12.6Hz,1H),2.88-2.78(m,3H),2.13(d,J=3.0Hz,1H),1.98(dddd,J=12.9,10.2,5.0,2 .7Hz,4H),1.91-1.69(m,6H),1.66-1.58(m,2H),1.55-1.38(m,2H),1.37-1.30(m,1H),1.28(d,J=2.0Hz,3H).13C NMR (151MHz, CDCl3) δ168.19,131.49,131.16,129.05,128.85,128.28,126.03,124.93,124.80,74.50,64.68,63.7 4,57.28,57.23,53.37,43.13,41.62,35.66,29.71,27.88,26.31,26.07,21.43,21.25,20.74.m / z:455.2693(M+1).

[0089] Compound Q12: (14R)-9-anthracite matrine, pale yellow powder, yield 40%. Melting point: 135.1℃-136.3℃. 1 H NMR (600MHz, CDCl3) δ8.64(dd,J=8.9,1.0Hz,2H),8.47(s,1H),8.02(dd,J=8.4,1.2Hz,2H),7.58(ddd,J=8.9,6.5,1.3Hz,2H),7.48(ddd ,J=8.4,6.5,1.0Hz,2H),6.15(d,J=11.2Hz,1H),5.80(d,J=11.2Hz,1H),4.48(dd,J=12.7,4.3Hz,1H),3.96(dd,J=10.7,5.2Hz,1H),3.8 1(td,J=10.0,5.7Hz,1H),3.16(t,J=12.7Hz,1H),2.83(dd,J=22.6,11.2Hz,2H),2.16(dtd,J=14.1,5.7,3.1Hz,1H),2.10(s,1H),2.03- 1.93(m,3H),1.88-1.83(m,1H),1.81-1.71(m,3H),1.58(dt,J=13.6,4.7Hz,1H),1.51-1.29(m,3H),1.28(s,4H),0.94-0.89(m,1H).13C NMR (151MHz, CDCl3) δ170.46,131.48,131.40,129.11,128.78,128.29,126.22,124.94,74.61,65.96,63.58 ,57.22,53.30,43.32,41.57,35.38,29.71,27.79,26.76,26.15,24.56,21.18,20.73.m / z:455.2671(M+1).

[0090] Figure 1 The images show the single-crystal diffraction patterns of compounds Q11 and Q12. The absolute configurations of the remaining compounds were determined based on the proton NMR spectra of Q11 and Q12.

[0091] Example 7

[0092] Q13 and Q14 were prepared using the method described in Example 1, and their structural identification data are as follows:

[0093] Compound Q13: (14S)-4-(4-morpholino)aniline matrine, yield 35%. Melting point: 162.2℃-163.0℃. 1H NMR (600MHz, CDCl3) δ6.91-6.79(m,2H),6.75-6.65(m,2H),4.30(dd,J=12.5,4.3Hz,1H),4.01(dd d,J=10.5,5.9,3.9Hz,1H),3.89-3.84(m,5H),3.79(dd,J=9.4,5.2Hz,1H),3.18(t,J=12.5Hz,1H) ,3.03(dd,J=5.9,3.7Hz,4H),2.90-2.76(m,3H),2.18(dt,J=16.6,4.2Hz,2H),2.07-1.89(m,5H), 1.82-1.67(m,5H),1.62(dt,J=12.9,3.7Hz,1H),1.55(dt,J=13.8,5.0Hz,1H),1.48-1.37(m,4H). 13 C NMR (151MHz, CDCl3) δ169.14,144.22,142.12,118.17,115.32,76.85,67.11,64.15,57.29,57.28,55. 50,53.42,51.13,43.37,41.04,35.95,27.74,26.76,24.58,21.35,21.17,20.69.m / z:425.2907(M+1).

[0094] Compound Q14: (14R)-4-(4-morpholino)aniline matrine, yellow powder, yield 39%. Melting point: 131.2℃-133.0℃. 1 H NMR (600MHz, CDCl3) δ6.86-6.82(m,2H),6.66-6.62(m,2H),4.35(dd,J=12.9,4.4Hz,1H),3.86-3. 83(m,5H),3.63-3.57(m,1H),3.14(t,J=12.7Hz,1H),3.02(dd,J=6.0,3.7Hz,4H),2.82(dddt,J=30 .0,11.5,4.2,2.0Hz,3H),2.47-2.38(m,1H),2.22(ddd,J=10.9,6.4,4.4Hz,1H),2.09(t,J=2.8Hz, 1H),2.02-1.90(m,3H),1.78-1.60(m,4H),1.58-1.51(m,3H),1.43(ddq,J=26.5,12.9,4.0Hz,5H). 13C NMR (151MHz, CDCl3) δ169.61,143.92,142.29,118.27,114.79,67.10,63.37,57.16,57.12,55. 50,53.69,51.20,43.97,42.14,35.30,27.72,26.89,25.91,21.15,20.74.m / z:425.2894(M+1).

[0095] Example 8

[0096] Q15 and Q16 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0097] Compound Q15: (14S)-4-bromoaniline matrine, a yellow oil, yield 33%. 1 H NMR (600MHz, CDCl3) δ7.27(d,J=8.5Hz,2H),6.53(d,J=8.6Hz,2H),5.20(s,1H),4.36(dd,J=12.8,4.4H z,1H),4.12-3.99(m,2H),3.89(td,J=10.2,6.1Hz,1H),3.68-3.58(m,1H),3.17(t,J=12.8Hz,1H),2.9 3-2.76(m,2H),2.42(dd,J=10.0,4.7Hz,1H),2.26(dd,J=11.1,5.5Hz,1H),2.11(s,1H),2.02-1.90(m, 3H),1.79-1.68(m,3H),1.67-1.61(m,1H),1.59-1.52(m,2H),1.52-1.46(m,2H),1.39(d,J=7.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ168.68,146.72,131.89,115.30,109.66,64.11,57.28,54.77,53.42,43.49, 41.00,35.98,31.63,29.71,29.66,27.73,26.79,24.24,21.34,21.16,20.68.m / z:418.1467(M+1).

[0098] Compound Q16: (14R)-4-bromoaniline matrine, a yellow oil, yield 35%. 1H NMR (600MHz, CDCl3) δ7.28-7.26(m,2H),6.60-6.51(m,2H),4.84(d,J=3.3Hz,1H),4.29(dd,J=12.5,4.3Hz,1H), 4.04(ddd,J=10.3,6.0,3.7Hz,1H),3.81(ddd,J=9.0,5.0,2.8Hz,1H),3.20(t,J=12.6Hz,1H),2.92-2.79(m,2H) ,2.28-2.17(m,2H),2.08-2.02(m,1H),1.99(ddd,J=14.6,9.4,3.0Hz,2H),1.92(dq,J=14.3,2.5Hz,1H),1.83-1 .68(m,3H),1.65(s,2H),1.63-1.53(m,1H),1.50-1.44(m,2H),1.43(s,1H),1.31(s,1H),1.28(d,J=2.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ169.16,146.70,131.90,115.01,109.34,63.35,57.11,54.79,53.72,43. 98,42.25,35.31,31.94,29.71,29.66,27.70,27.10,22.71,21.14,20.73.m / z:418.1468(M+1).

[0099] Example 9

[0100] Q17 and Q18 were prepared using the method described in Example 1, and their structural identification data are as follows:

[0101] Compound Q17: (14S)-3-aminobiphenylmatrine, pale yellow solid, yield 27%. Melting point: 143.7℃-145.2℃. 1H NMR (600MHz, CDCl3) δ7.68-7.52(m,2H),7.44(t,J=7.6Hz,2H),7.38-7.33(m,1H),7.28(t,J=7.9Hz,1H),7.07-6.92(m,1H),6.89(t,J=2.0Hz, 1H),6.69(dd,J=8.1,2.3Hz,1H),4.95(s,1H),4.32(dd,J=12.6,4.4Hz,1H),4.05(ddd,J=10.4,6.0,3.9Hz,1H),3.94(dd,J=9.5,5.2Hz,1H),3 .21(t,J=12.5Hz,1H),2.91-2.79(m,2H),2.28(ddt,J=13.5,5.5,3.1Hz,1H),2.21(d,J=3.0Hz,1H),2.10-1.91(m,5H),1.82(dddd,J=14.0,12 .1,9.4,2.9Hz,2H),1.75-1.69(m,2H),1.64(dt,J=12.6,3.7Hz,1H),1.55(tt,J=13.5,4.9Hz,1H),1.45(dddd,J=27.0,14.0,7.2,3.3Hz,3H). 13 C NMR (151MHz, CDCl3) δ148.08,142.41,141.82,129.56,128.60,127.23,127.12,117.23,112.73,112.63,64.1 5,57.31,54.87,53.45,43.45,41.06,35.96,27.76,26.80,24.53,21.42,21.18,20.70.m / z:416.2708(M+1).

[0102] Compound Q18: (14R)-3-aminobiphenylmatrine, yellow powder, yield 43%. Melting point: 123.7℃-124.7℃. 1H NMR (600MHz, CDCl3) δ7.68-7.53(m,2H),7.44(t,J=7.7Hz,2H),7.38-7.34(m,1H),7.28(t,J=7.8Hz,1H),6.98(dt,J=7. 7,1.1Hz,1H),6.67(ddd,J=8.1,2.4,0.9Hz,1H),5.32(s,1H),4.39(dd,J=12.8,4.4Hz,1H),3.91(td,J=10.1,6.7Hz,1H) ,3.82-3.68(m,1H),3.18(t,J=12.7Hz,1H),2.97-2.74(m,2H),2.58-2.47(m,1H),2.26(ddt,J=13.1,8.2,5.6Hz,1H),2. 11(d,J=2.9Hz,1H),2.06-1.92(m,3H),1.80-1.67(m,3H),1.68-1.55(m,3H),1.47(dddq,J=22.6,13.9,8.3,4.1Hz,5H). 13 C NMR (151MHz, CDCl3) δ169.40,148.08,142.44,141.87,129.58,128.60,127.23,127.11,116.96,112.35,6 3.39,57.19,54.90,53.77,43.99,42.25,35.35,27.75,26.75,25.94,21.19,20.77.m / z:416.2695(M+1).

[0103] Example 10

[0104] Q19 and Q20 were prepared using the method described in Example 1, and their structural identification data are as follows:

[0105] Compound Q19: (14S)-4-aminobiphenylmatrine, yellow solid, yield 37%. Melting point: 155.7℃-157.2℃. 1H NMR (600MHz, CDCl3) δ7.58-7.54(m,2H),7.49-7.45(m,2H),7.41(t,J=7.7Hz,2H),7.31-7.25(m,1H),6.78-6.75(m, 2H),4.92(s,1H),4.32(dd,J=12.5,4.3Hz,1H),4.05(ddd,J=10.4,5.9,3.7Hz,1H),3.92(dd,J=9.6,5.2Hz,1H),3.21 (t,J=12.5Hz,1H),2.93-2.79(m,3H),2.33-2.25(m,1H),2.22(t,J=3.0Hz,1H),2.15-1.90(m,6H),1.86-1.79(m,1H) ,1.75-1.69(m,2H),1.65(dt,J=9.0,4.1Hz,3H),1.57(dt,J=13.8,4.9Hz,1H),1.46-1.38(m,1H),0.97-0.84(m,1H). 13 C NMR (151MHz, CDCl3) δ168.91,147.15,141.25,128.63,127.91,126.36,126.10,113.98,64.16,57.30,57 .30,54.81,53.45,43.46,41.05,35.97,29.71,27.75,24.47,21.40,21.18,20.71.m / z:416.2674(M+1).

[0106] Compound Q20: (14R)-4-aminobiphenylmatrine, pale yellow solid. Yield 44%. Melting point: 133.6℃-134.9℃. 1H NMR (600MHz, CDCl3) δ7.58-7.54(m,2H),7.48-7.45(m,2H),7.41(t,J=7.7Hz,2H),7.27(s,1H),6.76-6.72(m,2H) ,5.28(s,1H),4.39(dd,J=12.8,4.4Hz,1H),3.91(td,J=10.3,6.1Hz,1H),3.77-3.72(m,1H),3.18(t,J=12.7Hz,1H ),2.85(dd,J=29.9,11.5Hz,2H),2.52(dt,J=9.5,4.5Hz,1H),2.31-2.24(m,1H),2.12(d,J=2.9Hz,1H),2.06-1.9 3(m,4H),1.79-1.73(m,1H),1.59(tt,J=11.0,9.7,3.3Hz,2H),1.53-1.45(m,3H),1.28(s,4H),0.94-0.88(m,1H). 13 C NMR (151MHz, CDCl3) δ169.37,147.14,141.28,130.64,128.62,127.92,126.33,126.06,113.70,63.40,57.1 9,57.15,54.83,53.77,44.00,42.24,35.34,29.71,27.74,26.66,25.95,21.18,20.76.m / z:416.2694(M+1).

[0107] Example 11

[0108] Q21 and Q22 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0109] Compound Q21: (14S)-4-chloroaminobiphenylmatrine, a yellow oil, yield 40%. 1H NMR (600MHz, CDCl3) δ7.15-7.11(m,2H),6.62-6.58(m,2H),4.83(s,1H),4.29(dd,J=12.6,4.3Hz,1H),4.03 (dt,J=10.7,4.7Hz,1H),3.81(dd,J=9.7,5.2Hz,1H),3.19(t,J=12.5Hz,1H),2.94-2.71(m,2H),2.24-2.17( m,2H),2.01(dddd,J=30.3,14.4,6.3,3.1Hz,4H),1.91(dt,J=14.3,2.5Hz,1H),1.79(dd,J=15.5,5.8Hz,1H) ,1.76-1.66(m,4H),1.55(tq,J=8.6,4.6,4.2Hz,1H),1.43(dtd,J=27.3,10.6,9.8,3.8Hz,4H),1.27(s,1H). 13 C NMR (151MHz, CDCl3) δ168.73,146.30,128.99,122.55,114.80,64.11,57.24,54.84,53.39, 43.44,40.98,35.95,29.71,27.70,26.74,24.28,21.34,21.11,20.63.m / z:374.2262(M+1).

[0110] Compound Q22: (14R)-4-chloroaminobiphenylmatrine, a yellow oil, yield 42%. 1 H NMR (600MHz, CDCl3) δ7.24-7.01(m,2H),6.66-6.43(m,2H),5.18(s,1H),4.36(dd,J=12.9,4.3Hz, 1H),3.88(td,J=10.4,6.2Hz,1H),3.67-3.54(m,1H),3.16(t,J=12.7Hz,1H),2.84(dddt,J=29.5,1 1.5,4.1,1.9Hz,2H),2.46-2.37(m,1H),2.24(ddd,J=10.5,6.2,4.1Hz,1H),2.11(t,J=2.8Hz,1H), 2.04-1.91(m,3H),1.79-1.68(m,3H),1.58-1.52(m,3H),1.50-1.44(m,4H),1.27(d,J=1.8Hz,1H). 13C NMR (151MHz, CDCl3) δ169.18,146.31,129.01,122.27,114.51,63.33,57.15,54.89,53.72, 43.97,42.23,35.32,29.71,27.71,26.48,25.92,25.89,21.14,20.73.m / z:374.2267(M+1).

[0111] Example 12

[0112] Q23 and Q24 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0113] Compound Q23: (14S)-4-iodoaminobiphenylmatrine, white powder, yield 41%. Melting point: 178.7℃-180.2℃. 1 H NMR (600MHz, CDCl3) δ7.47-7.41(m,2H),6.49-6.45(m,2H),4.86(s,1H),4.29(dd,J=12.5,4.3Hz,1H),4.04(ddd ,J=10.4,6.0,3.6Hz,1H),3.82(dd,J=9.7,5.2Hz,1H),3.20(t,J=12.5Hz,1H),2.84(dddt,J=28.8,11.5,4.0,2. 1Hz,2H),2.25-2.17(m,2H),2.07-1.96(m,4H),1.92(dt,J=14.4,2.6Hz,1H),1.83-1.76(m,1H),1.76-1.67(m,3 H),1.63(dt,J=12.7,3.7Hz,1H),1.56(dt,J=13.7,4.9Hz,1H),1.46(ddt,J=13.8,10.4,2.9Hz,3H),1.28(s,2H). 13 C NMR (151MHz, CDCl3) δ168.63,147.31,137.76,115.90,78.72,64.11,57.28,54.61,53.4 2,43.49,40.99,35.98,27.74,26.80,24.19,21.34,21.16,20.68.m / z:466.1671(M+1).

[0114] Compound Q24: (14R)-4-iodoaminobiphenylmatrine, white solid, yield 42%. Melting point: 173.7℃-174.7℃. 1H NMR (600MHz, CDCl3) δ7.54-7.37(m,2H),6.52-6.29(m,2H),5.20(s,1H),4.36(dd,J=12.9, 4.4Hz,1H),3.99-3.79(m,1H),3.64(dd,J=11.3,4.5Hz,1H),3.16(t,J=12.7Hz,1H),2.84( dd,J=29.4,11.4Hz,2H),2.48-2.37(m,1H),2.29-2.22(m,1H),2.11(s,1H),2.05-1.91(m, 3H),1.79-1.68(m,3H),1.57-1.53(m,2H),1.48(dt,J=14.0,4.7Hz,3H),1.30-1.26(m,2H). 13 C NMR (151MHz, CDCl3) δ169.11,147.27,137.76,115.64,78.34,63.35,57.15,54.62,53.73,4 3.97,42.24,35.32,29.71,27.71,26.34,25.92,25.89,21.14,20.73.m / z:466.1675(M+1).

[0115] Example 13

[0116] Q25 and Q26 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0117] Compound Q25: (14S)-4-chlorobenzoate matrine, a yellow oil, yield 38%. 1 H NMR (600MHz, CDCl3) δ8.03-7.97(m,2H),7.43-7.37(m,2H),5.43(dd,J=7.7,5.0Hz ,1H),4.33(dd,J=12.6,4.4Hz,1H),3.99(dt,J=11.1,5.7Hz,1H),3.17(t,J=12.6Hz ,1H),2.93-2.68(m,2H),2.22-2.13(m,2H),2.08-1.95(m,4H),1.94-1.84(m,3H), 1.78-1.61(m,4H),1.54(tt,J=13.6,4.7Hz,1H),1.45(dq,J=12.7,5.1,4.6Hz,3H). 13C NMR (151MHz, CDCl3) δ165.37,164.93,139.47,131.26,128.62,128.48,70.45,63.89,57.22, 53.28,42.65,41.57,35.66,27.65,26.64,24.07,21.30,21.11,20.65.m / z:403.2073(M+1).

[0118] Compound Q26: (14R)-4-chlorobenzoate matrine, a yellow oil, yield 40%. 1 H NMR (600MHz, CDCl3) δ8.08-8.03(m,2H),7.44-7.40(m,2H),5.44(dd,J=11.9,5.3Hz,1H),4.35(dd ,J=12.9,4.4Hz,1H),3.89(td,J=10.5,5.7Hz,1H),3.15(t,J=12.8Hz,1H),2.83(dddt,J=34.3,11. 6,4.1,1.9Hz,2H),2.36-2.24(m,2H),2.10(d,J=2.9Hz,1H),2.04-1.89(m,4H),1.73(ddd,J=16.8 ,8.2,2.9Hz,2H),1.69-1.62(m,2H),1.56(dddd,J=16.7,10.6,8.3,4.6Hz,2H),1.50-1.42(m,4H). 13 C NMR (151MHz, CDCl3) δ166.30,165.27,139.43,131.38,128.61,128.56,69.86,63.31,57.18,57. 14,53.32,43.67,41.67,35.03,27.69,26.03,25.50,25.12,21.13,20.74.m / z:403.2072(M+1).

[0119] Example 14

[0120] Q27 and Q28 were prepared using the method described in Example 1, and their structural identification data are as follows:

[0121] Compound Q27: (14S)-4-trifluoromethoxyaniline matrine, white powder, yield 33%. Melting point: 165.3℃-166.2℃. 1H NMR (600MHz, CDCl3) δ7.05 (d, J=8.6Hz, 2H), 6.67-6.63 (m, 2H), 4.89 (s, 1H), 4.30 (dd, J=12.6 ,4.3Hz,1H),4.05(ddd,J=10.3,6.0,3.7Hz,1H),3.83(dd,J=9.7,5.2Hz,1H),3.20(t,J=12.5H z,1H),2.85(dddd,J=29.2,11.4,4.1,1.8Hz,2H),2.24-2.20(m,2H),2.08-1.90(m,5H),1.83 -1.67(m,5H),1.59(dtt,J=45.1,13.6,4.4Hz,2H),1.44(dddt,J=22.7,18.3,8.5,3.9Hz,3H). 13 C NMR (151MHz, CDCl3) δ168.68,146.53,140.89,122.33,113.99,64.11,57.27,54.92,53. 42,43.48,41.02,35.98,27.73,26.79,24.33,21.36,21.16,20.68.m / z:424.2496(M+1).

[0122] Compound Q28: (14R)-4-trifluoromethoxyaniline matrine, white solid, yield 39%. Melting point: 143.7℃-144.2℃. 1 H NMR (600MHz, CDCl3) δ7.08-7.03(m,2H),6.64-6.58(m,2H),5.24(s,1H),4.37(dd,J= 12.9,4.4Hz,1H),3.90(td,J=10.2,6.3Hz,1H),3.71-3.59(m,1H),3.17(t,J=12.8Hz ,1H),2.85(dd,J=30.0,11.2Hz,2H),2.50-2.38(m,1H),2.26(tq,J=10.7,6.3,5.3Hz ,1H),2.11(d,J=2.8Hz,1H),2.05-1.91(m,3H),1.81-1.64(m,4H),1.60-1.42(m,8H). 13C NMR (151MHz, CDCl3) δ169.15,146.53,122.36,113.68,76.81,63.34,57.16,57.12,54.96,5 3.73,43.99,42.24,35.32,29.71,27.72,26.49,25.90,21.15,20.74.m / z:424.2491(M+1).

[0123] Example 15

[0124] Q29 and Q30 were prepared using the preparation method described in Example 1, and their structural identification data are as follows:

[0125] Compound Q29: (14S)-2-iodoaniline matrine, white solid, yield 41%. Melting point: 191.2℃-194.8℃. 1 H NMR (600MHz, CDCl3) δ7.69 (dd, J=7.8, 1.5Hz, 1H), 7.21 (ddd, J=8.5, 7.4, 1.5Hz, 1H ),6.64(dd,J=8.3,1.4Hz,1H),6.48(td,J=7.5,1.4Hz,1H),4.35-4.24(m,1H),4.04 (ddd,J=10.5,6.1,3.9Hz,1H),3.90(dt,J=9.1,4.5Hz,1H),3.19(t,J=12.5Hz,1H) ,2.83(dddt,J=29.8,11.5,4.0,2.0Hz,2H),2.25-2.17(m,2H),2.11-1.36(m,15H). 13 C NMR (151MHz, CDCl3) δ168.44,146.88,139.21,129.26,119.20,111.18,86.68,64.11,57.30,55. 08,53.46,43.42,41.13,35.82,27.73,26.80,24.26,21.49,21.19,20.72.m / z:466.1649(M+1).

[0126] Compound Q30: (14R)-2-iodoaniline matrine, white solid, yield 46%. Melting point: 167.3℃-168.8℃. 1H NMR (600MHz, CDCl3) δ7.71 (dd, J=7.8, 1.5Hz, 1H), 7.24-7.16 (m, 1H), 6.55-6.38 (m, 2H), 5.6 8(d,J=3.0Hz,1H),4.39(dd,J=12.8,4.4Hz,1H),3.90(td,J=10.4,6.1Hz,1H),3.70(dt,J=1 1.5, 3.8Hz, 1H), 3.18 (t, J=12.7Hz, 1H), 2.83 (dddt, J=29.7, 11.4, 4.1, 1.9Hz, 2H), 2.50-2. 41(m,1H),2.30-2.22(m,1H),2.10(t,J=2.9Hz,1H),2.04-1.90(m,3H),1.79-1.39(m,11H). 13 C NMR (151MHz, CDCl3) δ168.91,147.03,139.36,129.18,118.96,110.62,86.57,63.36,57.17,57.14, 55.29,53.67,44.04,42.35,35.38,27.78,26.38,25.99,25.94,21.19,20.78.m / z:466.1649(M+1).

[0127] Example 16

[0128] Q31 and Q32 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0129] Compound Q31: (14S)-2-chloroaniline matrine, pale yellow powder, yield 40%. Melting point: 179.3℃-182.5℃. 1H NMR (600MHz, CDCl3) δ7.27 (dd, J=7.8, 1.5Hz, 1H), 7.14 (td, J=7.8, 1.5Hz, 1H), 6.73 (dd, J=8.2, 1.4Hz, 1H), 6. 66(td,J=7.6,1.4Hz,1H),5.32(d,J=4.0Hz,1H),4.31(dd,J=12.6,4.3Hz,1H),4.03(dt,J=10.7,5.0Hz,1H),3. 92(dt,J=9.2,4.6Hz,1H),3.19(t,J=12.6Hz,1H),2.90-2.68(m,2H),2.21(dqt,J=12.2,5.2,3.0Hz,2H),2.08- 1.89(m,5H),1.83(ddt,J=13.7,7.5,2.6Hz,2H),1.76-1.50(m,5H),1.44(dddd,J=18.3,14.0,8.1,6.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ168.50,143.62,129.27,127.63,120.25,117.82,111.73,64.09,57.28,54 .50,53.45,43.37,41.15,35.84,27.72,26.75,24.44,21.47,21.17,20.70.m / z:374.2191(M+1).

[0130] Compound Q32: (14R)-2-chloroaniline matrine, pale yellow solid, yield 47%. Melting point: 144.2℃-145.5℃. 1H NMR (600MHz, CDCl3) δ7.28 (dd, J=7.9, 1.5Hz, 1H), 7.12 (td, J=7.8, 1.5Hz, 1H), 6.66 (td, J=7.6, 1.4Hz, 1H), 6.60(dd,J=8.2,1.3Hz,1H),5.72(d,J=3.4Hz,1H),4.38(dd,J=12.8,4.4Hz,1H),3.90(td,J=10.4,6.1Hz,1 H),3.72(dt,J=11.7,4.0Hz,1H),3.17(t,J=12.7Hz,1H),2.83(dddt,J=29.7,11.4,4.0,1.9Hz,2H),2.50-2 .41(m,1H),2.33-2.21(m,1H),2.13-2.05(m,1H),2.05-1.89(m,3H),1.82-1.53(m,7H),1.51-1.40(m,5H). 13 C NMR (151MHz, CDCl3) δ168.98,143.73,129.38,127.56,120.41,117.60,111.25,77.07,63.35,57.17 ,54.72,53.69,44.00,42.26,35.34,27.76,26.53,25.96,25.95,21.18,20.77.m / z:374.2151(M+1).

[0131] Example 17

[0132] Q33 and Q34 were prepared using the preparation method described in Example 1. Their structural identification data are as follows:

[0133] Compound Q33: (14S)-4-bromobenzoate matrine, a yellow oil, yield 39%. 1 H NMR (600MHz, CDCl3) δ8.04-7.86(m,2H),7.68-7.47(m,2H),5.44(dd,J=7.7,5.0Hz,1H),4.34(dd,J=12.6,4.4Hz,1H),4.00(dt,J=11.1,5.6Hz,1H), 3.18(t,J=12.6Hz,1H),2.93-2.76(m,3H),2.23-2.13(m,2H),2.08-1.85( m,7H),1.77-1.61(m,5H),1.55(tt,J=13.6,4.9Hz,1H),1.49-1.44(m,3H). 13C NMR (151MHz, CDCl3) δ165.36,165.09,131.63,131.40,128.94,128.18,70.48,63.91,57.24, 53.29,42.67,41.59,35.68,27.67,26.66,24.07,21.31,21.13,20.68.m / z:447.1434(M+1).

[0134] Compound Q34: (14R)-4-bromobenzoate matrine, a yellow oil, yield 41%. 1 H NMR (600MHz, CDCl3) δ8.03-7.91(m,2H),7.63-7.55(m,2H),5.44(dd,J=11.9,5.3Hz,1H),4.35( dd,J=12.9,4.5Hz,1H),3.89(td,J=10.5,5.7Hz,1H),3.15(t,J=12.8Hz,1H),2.84(dddt,J=34. 3,11.5,4.0,1.8Hz,2H),2.29(ddtd,J=31.3,12.9,4.9,3.1Hz,2H),2.10(d,J=2.9Hz,1H),2.04 -1.89(m,4H),1.76-1.63(m,5H),1.56(dddd,J=13.8,10.5,6.2,4.1Hz,2H),1.50-1.44(m,3H). 13 C NMR (151MHz, CDCl3) δ166.28,165.42,131.61,131.51,129.01,128.13,69.89,63.31,57.18,57. 14,53.32,43.67,41.68,35.04,27.69,26.03,25.49,25.12,21.13,20.74.m / z:447.1416(M+1).

[0135] The structural formulas of the 14-position matrine derivatives prepared in Examples 1-17 are shown in Table 1.

[0136] Table 1

[0137]

[0138]

[0139]

[0140]

[0141] Comparative Example 1

[0142] Compared to Example 1, this comparative example only replaced the catalyst copper hexafluorophosphate tetraacetonitrile with copper acetate, while other conditions were the same as in Example 1.

[0143] When copper acetate is used as a catalyst, the overall yield of the product is 12%.

[0144] Comparative Example 2

[0145] Compared to Example 1, this comparative example only replaced the catalyst copper hexafluorophosphate tetraacetonitrile with palladium acetate, while other conditions were the same as in Example 1.

[0146] When palladium acetate is used as a catalyst, the overall yield of the product is 5%.

[0147] Comparative Example 3

[0148] Compared to Example 1, this comparative example only replaced the catalyst copper hexafluorophosphate tetraacetonitrile with silver acetate, while other conditions were the same as in Example 1.

[0149] When silver acetate is used as a catalyst, the overall yield of the product is less than 5%.

[0150] Effect verification

[0151] The in vitro antitumor activity of the matrine derivatives prepared in Examples 1-17 was studied. The tumors used were human hepatocellular carcinoma cells (HepG2) and rat glioma cells (C6), both derived from the Cell Bank of the Chinese Academy of Sciences (Shanghai).

[0152] Experimental Methods: All cells were cultured in McCoy5A medium containing 10% FBS and 1% penicillin-streptomycin, and placed in a cell culture incubator at 37°C and 5% CO2. The MTT assay was performed, and the chiral derivative of matrine was dissolved and diluted to the desired concentration using dimethyl sulfoxide (DMSO). A dish of cells in good growth condition was taken, and trypsin was added to prepare a solution containing 2 × 10⁻⁶ cells per milliliter. 4 -4×10 4Cell suspensions were prepared and seeded into 96-well plates. A blank control group (matrine) and a drug treatment group (150 μL) were established, with three parallel wells in each group. The cells were placed in a cell culture incubator at 37℃ and 5% CO2. After 24 hours, matrine derivatives at concentrations of 100 μmol / L, 50 μmol / L, 25 μmol / L, 12.5 μmol / L, 6.25 μmol / L, and 3.125 μmol / L, and matrine at concentrations of 20 mmol / L, 10 mmol / L, 5 mmol / L, 2.5 mmol / L, 1.25 mmol / L, and 0.625 mmol / L were added, respectively. After culturing for another 48 hours, 15 μL of 5 mg / mL LMT (thiazolyl blue) was added to each well, and the cells were incubated for 4 hours. The supernatant was discarded, and 150 μL of LDMSO was added. The mixture was shaken and the absorbance of each well was measured at 490 nm using a microplate reader. The cell inhibition rate was calculated using the following formula:

[0153]

[0154] The above experiment was repeated three times, and the IC was calculated using the Blies method. 50 value.

[0155] The results of the inhibitory effects of the target compound on the proliferation of HepG2 and C6 cells are shown in Table 2.

[0156] Table 2

[0157]

[0158]

[0159] Conclusion: Experimental data show that most of the synthesized matrine derivatives have good antitumor activity. When matrine was used as a control drug and the target compounds were administered, the inhibition rates of the compounds were compared. It was found that Q4, Q12, Q17, and Q20 had more significant and stronger inhibitory effects on HepG-2 and C6 cells, and could have highly efficient antitumor inhibitory activity.

[0160] The above are merely preferred embodiments of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A chiral derivative of matrine at position 14, characterized in that, The general structural formula is: 、 ； In the general formula of the structure, X = NH or ;in, C is connected to one end of R; R is a substituted or unsubstituted phenyl, biphenyl, naphthyl, anthraceneyl, or pyridyl group; wherein the substituted group is a halogroup, morpholino, or trifluoromethoxy group; In the general formula of the structure, when X=0, R is... .

2. The matrine chiral derivative at position 14 according to claim 1, characterized in that, When X=0, R is selected from any of the following structures: 、 、 、 、 。 3. The matrine chiral derivative at position 14 according to claim 1, characterized in that, When X=NH, R is selected from any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 。 4. The method for preparing the 14-position chiral derivative of matrine according to any one of claims 1-3, characterized in that, Includes the following steps: (1) Under sodium bis(trimethylsilyl)amino, matrine undergoes a nucleophilic reaction with tert-butyl nitrite to give the intermediate matrine oxime I, whose structural formula is: ; (2) The intermediate matrine oxime I is dehydrated with hydrazine hydrate to obtain intermediate matrine hydrazone II, the structural formula of which is: ; (3) The intermediate matrine hydrazone II undergoes an oxidation reaction with manganese dioxide to obtain the intermediate matrine diazo III, the structural formula of which is: ; (4) Under the catalysis of copper tetraacetonitrile hexafluorophosphate, the intermediate matrine diazo III is reacted with amine, alcohol or acid compound by insertion reaction, and then concentrated and separated to obtain the 14-chiral derivative of matrine.

5. The method for preparing the 14-position chiral derivative of matrine according to claim 4, characterized in that, The mass-to-volume ratio of matrine to tert-butyl nitrite in step (1) is (5~6) g: 10 mL.

6. The method for preparing the 14-position chiral derivative of matrine according to claim 4, characterized in that, The mass-to-volume ratio of the intermediate matrine oxime I to hydrazine hydrate in step (2) is 1 g: 6 mL.

7. The method for preparing the 14-position chiral derivative of matrine according to claim 4, characterized in that, The mass ratio of the intermediate matrine hydrazone II to manganese dioxide in step (3) is 1:

4.

8. The method for preparing the 14-position chiral derivative of matrine according to claim 4, characterized in that, The molar ratio of matrine diazonium III, the intermediate mentioned in step (4), to an amine, alcohol, or acid compound is (1~1.2):(1.2~1.4).

9. The use of the 14-position chiral derivative of matrine as described in any one of claims 1-3 in the preparation of anticancer drugs, characterized in that, The anticancer drug mentioned is an anti-liver cancer drug or an anti-brain cancer drug.

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